Topical retinoids have been widely used for multiple cutaneous disorders, as reported in A. Haas et al. “Selected Therapeutic Applications of Topical Tretinoin.” JAAD, 15:870 (1986) (See Table I below). In many instances, the application of tretinoin has alleviated or induced remission in many such conditions, although these disorders reflect a variety of pathogenic mechanisms.
TABLE ISelected Therapeutic Application of Topical TretinoinDisorders with altered keratinizationAcneiform follicular, or nevoidNevus comdeonicusSenile comedonesSteroid folliculitisPsuedofolliculitisFox-Fordyce diseaseHair castsMonilethrixAlopeciaThrichiostasis spinulosaLinear verrucous nevusIchthyosiformEpidermolytic hyperkeratosis(congenital ichthyosiform erythroderma)Ichthyosis vulgarisLamellar ichthyosisX-linked ichthyosisPsoriasiform, hyperkeratotic, or dyskeratoticAcanthosis and psuedoachanthosisnigricansCallositesKeratosis follicularis (Darier's)Keratosis palmaris et plantarisKyrle's diseasePsoriasisReactive perforating collagenosisInfectious/inflammatory disordersMolluscum contagiosumFlat wartsPlantar wartsTinea versicolorLeg ulcersKeloids and hypertrophic scarsMucecutaneous disordersGeographic tongueLichen planusLeukoplakiaXerophthalmia (dry eye)Hairy leukoplakiaPigmentation disordersEphelidesMelasmaPostinflammatory hyperpigmentationMalignant and premalignant disordersActinic keratoses, photoagingKeratoacanthomasMelanomasCertival dysplasisBasal cell epithelioma
It has been demonstrated that prolonged topical application of Vitamin A acid (tretinoin or all-trans retinoic acid) is effective in the treatment of acne (See U.S. Pat. No. 3,729,568 and Kligman, A. M., “Topical Vitamin A Acid in Acne Vulgaris.” Arch. Derm., 99: 469-476 (1969)). Kligman utilizes a composition in which Vitamin A acid is dispersed in a water miscible (substantially oil- and fat-free) liquid carrier having high solvating action. The topical application of this Vitamin A acid composition causes irritation of the skin in the treated areas. A presently available gel form with alcohol base or cream formulation also causes irritation. (See U.S. Pat. Nos. 3,906,108 and 4,247,547.)
A cream formulation of tretinoin is presently approved and is commercially available from Ortho Pharmaceutical Company under the trademark RETIN-A. It contains a therapeutically effective amount of tretinoin, a hydrophobic material selected from the liquid and solid fatty acids, fatty alcohols, fatty acid esters, pharmaceutical grades of waxes and hydrocarbons, the latter ranging from liquids through semisolids, such as petrolatum, to solids, and the like, a non-ionic emulsifier, xanthan gum, a preservative, an antioxidant and water. This formulation is more generally acceptable in a low dose 0.025% formulation, but it is still unacceptable to certain individuals with sensitive skin for continued daily applications.
Furthermore, the above tretinoin cream is relatively dense and pasty, and the pharmaceutical base is not elegant. The necessity to stabilize the cream with xanthan gum and to apply daily or twice daily a fatty substrate to the skin leaves a greasy film with a pasty residue.
Therefore, the problem has been to find vehicles for retinoids, particularly tretinoin, and other irritating active ingredients in which the active ingredient would remain stable and non-oxidized in the presence of large amounts of water, while dramatically reducing the amount of irritation caused by the active ingredient. It is also desirable to have a vehicle which can provide sufficient hydration to allow good percutaneous absorption, while at the same time allowing the active ingredient to be spread very thinly over the skin.